Soft gelatin capsules, commonly referred to as softgels and seamless soft gelatin capsules, are each one piece capsules containing pharmaceutically acceptable actives or other compounds in a liquid or semi-liquid state. These capsules are fashioned, filled and sealed in one continuous operation. Soft gelatin capsules containing liquid pharmaceutical compositions provide an excellent system for the delivery of pharmaceutically acceptable actives. Soft gelatin capsules are a preferred dosage form for accurately dispensing liquids, offering a simple means of masking the unpleasant taste and aromas of many pharmaceutically acceptable actives. Soft gelatin capsules are also convenient, portable and easy to swallow.
Upon ingestion into the gastrointestinal tract the gelatin capsule ruptures releasing its contents. Unlike solids, softgels which contain a liquid do not first have to disintegrate prior to exhibiting a pharmacological action.
Soft gelatin capsules provide accurate and uniform delivery of a unit dose of a pharmaceutically acceptable active, an advantage which becomes especially important when delivering relatively small amounts of pharmaceutically acceptable actives. Soft gelatin capsules are also aesthetically appealing, especially when filled with a transparent liquid.
However, despite these advantages it is not always possible to prepare a liquid composition of the desired pharmaceutically acceptable active. Soft gelatin capsules are limited by the selection of solvents available for solubilizing and suspending pharmaceutically acceptable actives due to toxicity and capsule volume considerations.
Various methods have been employed to overcome this downfall. See U.S. Pat. No. 4,794,117, to Corbiere, issued Dec. 27, 1988; U.S. Pat. NO. 4,690,823, to Lohner et al., issued Sep. 1, 1987; U.S. Pat. No. 3,784,684, to Bossert et al., issued Jan. 8, 1974; PCT Application No. WO88/02625, to Yu et al., published Apr. 21, 1988; European Patent Application No. 152,292, to Rogers, published Aug. 21, 1985. U.S. Pat. No. 3,865,603, to Szymanski et al., issued Feb. 11, 1975; U.S. Pat. No. 2,580,683, to Kreuger, issued Jan. 1, 1952; Japanese Pat. No. 84044096, to Morishita, issued Jan. 26, 1984 and U.S. Pat. No. 5,141,961, to Coapman, issued Aug. 25, 1992.
The solvent system of the present invention has significant solvating properties able to dissolve relatively large quantities of pharmaceutically acceptable actives; producing concentrated solvent-active mixtures. Previous solvent systems utilized common solvents such as propylene glycol and polyethylene glycols; each providing excellent solvency but neither being completely appropriate for an important category of pharmaceutically acceptable active agents, the nonsteroidal anti-inflammatory compounds. Without being limited by theory, it is believed that many nonsteroidal anti-inflammatory compounds, like numerous other pharmaceutically acceptable actives, are strong acids which react with hydroxylated and poly-hydroxylated solvent and plasticizer species such as propylene glycol, polyethylene glycols and glycerin forming the pro-drug ester of the active compound. The present inventor has found tri-esters, when pared with polyvinylpyrrolidone creates an excellent solvent system for, but not limited to, nonsteroidal anti-inflammatory compounds and other acidic pharmaceutically acceptable actives, without the drawbacks of solvents containing reactive hydroxyl groups. Additionally, these tri-esterpolyvinylpyrrolidone systems allow for the facilitated selection of a plasticizer, by being nonsolvents for glycerin and possibly other plasticizers commonly used in soft gelatin capsule manufacturing. By being a nonsolvent, the tri-ester-polyvinylpyrrolidone system creates a barrier preventing the migration of the plasticizer from the soft gelatin shell into the pharmaceutically acceptable active/solvent fill.
Another advantage of the present tri-ester-polyvinylpyrrolidone solvent system is the tri-ester's water tolerance. This low water tolerance allows for the inclusion of additional water soluble pharmaceutically acceptable actives, expanding the range of activity of a single composition.
It is an object of the present invention to provide pharmaceutical compositions containing at least one pharmaceutically acceptable active in a mixture of a tri-ester and polyvinylpyrrolidone. Another object of the present invention is to provide a process for solubilizing or suspending at least one pharmaceutically acceptable active in a mixture of a tri-ester and polyvinylpyrrolidone. A further object of the present invention is to depict a process for preparing soft gelatin capsules containing a composition comprising at least one pharmaceutically acceptable active in a mixture of a tri-ester and polyvinylpyrrolidone; the soft gelatin shell being optionally transparent. A still further object of the present invention is to provide soft gelatin capsules containing at least one pharmaceutically acceptable active in a mixture of a tri-ester and polyvinylpyrrolidone, in which the soft gelatin shell is optionally transparent. These and other objects of this invention will become apparent in light of the following disclosure.